CN102603683A - Furan compound and preparation method and application of furan compound - Google Patents
Furan compound and preparation method and application of furan compound Download PDFInfo
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Abstract
The invention discloses a furan compound as well as a preparation method and application of the furan compound. The furan compound includes a compound represented by general formula (I) or general formula (II) or a pharmaceutical salt of the compound, wherein Ar1 refers to any one of various substituted aromatic rings, preferably refers to 2,4-dichlorphenyl, 4-chlorphenyl or 4-bromophenyl; Ar2 refers to any one of substituents of various substituted aromatic ring, preferably refers to phenyl, 4-fluorophenyl, 2-chlorphenyl, 4-chlorphenyl or 3-methoxyphenyl; and Ar3 refers to any one of various substituted aromatic rings, preferably refers to pyridine, 4-chlorphenyl and furan. The furan compound can be applied to drugs resisting to AI-2 quorum sensing, and the preparation method of the furan compound is mild in reaction conditions, cheap and easily accessible in raw materials, and simple in operation and post-processing.
Description
Technical field
The present invention relates to furan derivative, preparation method and, belong to anti-AI-2 type quorum sensing technical field of pharmaceuticals as the application of AI-2 quorum sensing suppressor factor.
Background technology
The quorum sensing of bacterium (Quorum Sensing) is that bacterium passes through excretory solubility signaling molecule (autoinducer AI) detects population density, and then coordinates a kind of information interchange mechanism of bacterium living beings function.When population density reaches certain threshold value; Bacterium is through the existence of intracellular receptor perception AI; Along with the increase of population density, the concentration of the AI signaling molecule that accumulates in the environment also raises accordingly, and bacterium is made a response when reaching certain threshold value; Therefore these signaling molecules are detected, in colony's scope with regard to more adjustable Expression of Related Genes.[Waters，C.M.；Bassler，B.L.?Quorum?sensing：Cell-to-cell?communication?in?bacteria.Annu.Rev.Cell.Dev.Biol.2005，21，319-346]。Present difference according to bacterium synthetic signaling molecule and induction mechanism; The agent of quorum sensing self-induction mainly is divided into 3 types: (1) Gram-negative bacteria often utilizes homoserinelactone class material (acyl-homoserine lactones; AHL also claims AI-1) as alternative self-induction agent in planting; (2) gram-positive microorganism then utilizes self-induction peptide (autoinducing peptides, alternative self-induction agent in AIP) conduct is planted more; (3) also having a kind of is the self-induction agent AI-2 that Gram-negative bacteria and gram-positive microorganism all exist, and its structure is a furans keto acyl boric acid diester, is applied to information interchange between the bacterium kind, also has self-induction agent such as AI-3, PQS, DSF, PAME in addition.
It is important related that quorum sensing system and the mechanism of causing a disease of pathogenic bacterium have, such as the secretion virulence factor, form microbial film, produce resistance etc.If can pass through molecular designing, some specific quorum sensing suppressor factor of chemosynthesis disturb colony's induction system, suppress the growth metabolism of pathogenic bacterium, thereby reach the purpose of treatment or prevention of bacterial property disease.This method is different from traditional usually " kills " bacterium with antibiosis, does not have microbiotic such as resistance generation and uses all drawbacks of being brought.Therefore, representing development trend [Rasmussen, the T.B. of antibacterials research at present to the medicament research and development of quorum sensing mechanism; Givskov, M.Quorum sensing inhibitors:a bargain of effects.Microbiology 2006,152,895-904.].In the colony induction of many types, what at present the new drug development future is arranged most is the AI-2 type.As stated, AI-2 is the self-induction agent that a kind of Gram-negative bacteria and gram-positive microorganism all exist, and the bacterial classification that relates to is extensive, confirms at present, has at least 40 various bacteria can synthesize and discern AI-2.Therefore,, can brand-new action target and mechanism of action be provided, make the discovery of finding wide spectrum and anti-drug resistance antimicrobial drug become possible [Ni, N. for the antibacterials exploitation through research to AI-2 type quorum sensing control methods; Li, M.; Wang, J.; Wang, B.Inhibitors and antagonists of bacterial quorum sensing.Med Res Rev 2009,29,65-124.].
Summary of the invention
The objective of the invention is for overcoming the deficiency of above-mentioned prior art, a kind of furfuran compound and preparation method thereof and the application in the medicine of preparation AI-2 type quorum sensing suppressor factor are provided.
The receptor protein LuxPQ of the selected AI-2 type quorum sensing of this patent is a target; Integrated use CAD and isostere principle; Principles such as the quasi-medicated property principle of while bound drug and ADMET character; Design, synthesize furans AI-2 type quorum sensing suppressor factor, and its biological activity is carried out system evaluation, to obtain the tool drugs molecule of research regulation and control AI-2 type quorum sensing system with brand new type; And the novel antibacterial lead compound of acquisition highly selective, wide spectrum and overriding resistance, for further antibacterials research and development lay the foundation.
The present invention is directed to LuxPQ albumen, utilize area of computer aided medicinal design principle design to synthesize a series of novel furan classes and hydrochloride thereof, general structure is following:
For realizing above-mentioned purpose, the present invention adopts following technical proposals:
A kind of furfuran compound has general structure (I) or general structure (II) or its hydrochloride
Wherein, Ar
1Be various substituted aromatic rings, Ar
2Be various substituted aromatic rings, Ar
3Be various substituted aromatic rings.
Preferably, Ar wherein
1Be 2,4 dichloro benzene base, 4-chloro-phenyl-or 4-bromophenyl; Ar
2Be phenyl, 4-fluorophenyl, 2-chloro-phenyl-, 4-chloro-phenyl-or 3-p-methoxy-phenyl; Ar
3Be pyridine, 4-chloro-phenyl-or furans.
Further, furfuran compound of the present invention is following compound:
N-(5-(2,4 dichloro benzene base)-furfuryl)-4-chlorobenzamide (3a)
N-(5-(4-chloro-phenyl-)-furfuryl)-4-chlorobenzamide (3b)
N-(5-(4-bromophenyl)-furfuryl)-4-chlorobenzamide (3c)
N-(5-(2,4 dichloro benzene base)-furfuryl)-furoamide (3d)
N-(5-(4-chloro-phenyl-)-furfuryl)-furoamide (3e)
N-(5-(4-bromophenyl)-furfuryl)-furoamide (3f)
N-(5-(2,4 dichloro benzene base)-furfuryl)-vitamin PP (3g)
N-(5-(4-chloro-phenyl-)-furfuryl)-vitamin PP (3h)
N-(5-(4-bromophenyl)-furfuryl)-vitamin PP (3i)
N-benzyl-5-(2,4 dichloro benzene base)-2-furylamine hydrochloride (5a),
N-benzyl-5-(4-chloro-phenyl-)-2-furylamine hydrochloride (5b),
N-benzyl-5-(4-bromophenyl)-2-furylamine hydrochloride (5c),
N-4-luorobenzyl-5-(2,4 dichloro benzene base)-2-furylamine hydrochloride (5d),
N-4-luorobenzyl-5-(4-chloro-phenyl-)-2-furylamine hydrochloride (5e),
N-4-luorobenzyl-5-(4-bromophenyl)-2-furylamine hydrochloride (5f),
N-2-benzyl chloride base-5-(2,4 dichloro benzene base)-2-furylamine hydrochloride (5g),
N-2-benzyl chloride base-5-(4-chloro-phenyl-)-2-furylamine hydrochloride (5h),
N-2-benzyl chloride base-5-(4-bromophenyl)-2-furylamine hydrochloride (5i),
N-4-benzyl chloride base-5-(2,4 dichloro benzene base)-2-furylamine hydrochloride (5j),
N-4-benzyl chloride base-5-(4-chloro-phenyl-)-2-furylamine hydrochloride (5k),
N-4-benzyl chloride base-5-(4-bromophenyl)-2-furylamine hydrochloride (5l),
N-3-methoxy-benzyl-5-(2,4 dichloro benzene base)-2-furylamine hydrochloride (5m),
N-3-methoxy-benzyl-5-(4-chloro-phenyl-)-2-furylamine hydrochloride (5n),
N-3-methoxy-benzyl-5-(4-bromophenyl)-2-furylamine hydrochloride (5o).
The preparation method of a kind of furfuran compound provided by the present invention, wherein the preparation method of general formula I may further comprise the steps:
(1) with the substituted aniline raw material, at acidic conditions and NaNO
2Effect generates diazonium salt down, under the cuprous chloride effect, generates benzofurane formaldehyde with furfural generation linked reaction then.
(2) the substituted benzylamine generation of benzofurane formaldehyde and aromatic ring nucleophilic addition gets azomethine, generates target compound or continues to make it into hydrochloride through sodium borohydride reduction.
Preferably, the substituted benzylamine of said aromatic ring is selected from 2,4 dichloro aniline, 4-chlorobenzene aniline, 4-bromobenzene aniline.The substituted benzylamine of said aromatic ring is selected from benzylamine, 4-flunamine, 2-chlorobenzylamine, 4-chlorobenzylamine or 3-methoxybenzylamine.
The preparation method of a kind of furfuran compound provided by the present invention, wherein the preparation method of general formula I I may further comprise the steps:
(1) with the substituted aniline raw material, at acidic conditions and NaNO
2Effect generates diazonium salt down, under the cuprous chloride effect, generates the benzofurane methylamine hydrochloride with chaff amine generation linked reaction then.
(3) fragrant formyl chloride is dissolved in the THF, slowly drips in the tetrahydrofuran solution of benzofurane methylamine hydrochloride and triethylamine again, stirring reaction obtains target compound through conventional means separation and purification again.
Preferably, said substituted aniline is selected from 2,4 dichloro aniline, 4-chlorobenzene aniline, 4-bromobenzene aniline.Said fragrant formyl chloride is selected from parachlorobenzoyl chloride, furoyl chloride or nicotinoyl chlorine.
Further specify technical scheme of the present invention below:
The synthetic route of furfuran compound is following:
1. midbody (4) preparation method (benzofurane formaldehyde):
With substituted aniline (10.0mmol) add hydrochloric acid (25.0mL, 4.8mol/L) in, and heated and stirred after dissolving back question response liquid is cooled to room temperature naturally, places cryosel to bathe to dissolving, the adularescent solid is separated out.(10.0ml, 1mol/L), solution is clarified gradually, finishes to continue to stir 10 minutes, gets the substituted aniline diazonium salt in reaction flask, to drip sodium nitrite solution gradually.In above-mentioned solution, drip furfural (1.44g, 15.0mmol) and the cuprous chloride aqueous solution (10mL 0.2mol/L), lasts 0.5 hour.After dropwising, rise to room temperature naturally.Constantly there is nitrogen to emit in the reaction process.React and emitted the back stopped reaction to no longer including nitrogen in 10 hours, filter, filter cake is used recrystallizing methanol at last with unsaturated carbonate potassium solution, petroleum ether, promptly obtains midbody (4)---benzofurane formaldehyde.
2. the preparation method of target compound (5) (general formula I I):
Midbody (4) (1.0mmol) is joined in the 20mL methyl alcohol, and ultrasonic hydrotropy under the room temperature condition, slowly drips the substituted benzylamine of aromatic ring (1.4mmol) in reaction flask, drip and finish, and moves to and continues reaction in 40 ℃ of oil baths, and reaction lasts 3 hours.Question response fully after, shift out after oil bath is cooled to room temperature naturally, place cryosel to bathe; Be cooled to below 0 ℃, gradation add block Peng Qinghuana (0.062g, 1.5mmol); Finish, keep continuing below 0 ℃ to stir 10 minutes, move to room temperature again; Continue reaction 10 hours, react completely stopped reaction.Vacuum is drained, and gets yellow solid, and column chromatography gets faint yellow oily thing, and the stationary phase of column chromatography is a silica gel, and moving phase is sherwood oil: ETHYLE ACETATE=20: 1～2: 1.Add an amount of saturated hydrogenchloride-ethanolic soln to above-mentioned oily matter, separate out white solid.The washing of filter cake ETHYLE ACETATE obtains target compound (5).
3. the preparation method of midbody (2) (benzofurane methylamine hydrochloride):
With substituted aniline (10.0mmol) add hydrochloric acid (25.0mL, 4.8mol/L) in, and heated and stirred after dissolving back question response liquid is cooled to room temperature naturally, places cryosel to bathe to dissolving, and is cooled to below 0 ℃, the adularescent solid is separated out.(10.0ml, 1mol/L), solution is clarified gradually, finishes, and keeps continuing below 0 ℃ to stir 10 minutes, gets diazonium salt in reaction flask, to drip sodium nitrite solution gradually.In above-mentioned solution, drip chaff amine (1.27g, 13.0mmol) and the cuprous chloride aqueous solution (10mL 0.2mol/L), lasts 0.5 hour.After dropwising, rise to room temperature naturally.Nitrogen gas generation is constantly arranged in the reaction process, have brown materials to generate, react 30 hours, react completely stopped reaction to no longer including nitrogen gas generation.Filter, filter cake is used recrystallizing methanol at last with unsaturated carbonate potassium solution, petroleum ether, promptly obtains midbody (2)---benzofurane methylamine hydrochloride.
4. preparing method's (general formula I) of target compound (3):
Midbody (2) (0.66mmol) is joined in the anhydrous tetrahydro furan (20mL), place ice bath to make its temperature be lower than 0 ℃, stirring and dissolving drips triethylamine (1mL) in reaction flask, the solution muddy shape that is white in color.Slowly drip fragrant formyl chloride (0.91mmol) to above-mentioned solution, drip and finish, keep continuing below 0 ℃ to stir 10 minutes, move to room temperature again, reacted 10 hours, react completely stopped reaction.Add 50mL water, solution has the muddy clarification that becomes, and becomes muddy subsequently again, crosses and filters yellow solid, uses recrystallizing methanol, is target compound (3).
Simultaneously, the invention still further relates to the application of above-mentioned furfuran compound in the medicine of the anti-AI-2 quorum sensing of preparation.
A kind of anti-AI-2 quorum sensing pharmaceutical composition comprises like above-mentioned furfuran compound and one or more pharmaceutically acceptable carriers or vehicle.
Can be a kind of mammiferous pharmaceutical composition of orally give that is suitable for, comprise above-mentioned furfuran compound and one or more pharmaceutically acceptable carriers or vehicle.
Also can be that a kind of parenteral that is suitable for gives mammiferous pharmaceutical composition, comprise above-mentioned furfuran compound and one or more pharmaceutically acceptable carriers or vehicle.
Furan derivatives of the present invention can free form or is existed with salt form.Pharmacy acceptable salt of the known chemical compound lot type of those skilled in the art and preparation method thereof.Pharmacy acceptable salt comprises conventional avirulent salt, and the season that comprises such compound alkali and inorganic or organic acid formation is by salt.
Compound of the present invention can form hydrate or solvate.The one skilled in the art known with compound formed hydrate or form the method for solvate when in solution, concentrating during with the water freeze-drying with appropriate organic solvent.
The present invention comprises the medicine that contains the therapeutic dose The compounds of this invention and the pharmaceutical composition of one or more pharmaceutically acceptable carriers and/or vehicle.Carrier comprises like salt solution, BS, and glucose, water, glycerine, ethanol and their binding substances, hereinafter is discussed in more detail.If desired, said composition can also comprise wetting agent or emulsifying agent in a small amount, or the pH buffer reagent.Said composition can be liquid, suspension-s, emulsion, tablet, pill, capsule, extended release preparation or powder.Said composition can be mixed with suppository with traditional firewood mixture and carrier such as triglyceride.Oral prepns can comprise the mannitol of standard vector such as medicine grade, lactose, starch, Magnesium Stearate, soluble saccharin, Mierocrystalline cellulose and magnesiumcarbonate or the like.Preparation and deciding optionally, preparation can design mixing, granulation and compression or solvent components.In another approach, said composition can be mixed with nano particle.
The pharmaceutical carrier that uses can for, for example, solid or liquid.
The typical solid carrier comprises lactose, terra alba, sucrose, talcum, gel, agar, pectin, gum arabic, Magnesium Stearate, Triple Pressed Stearic Acid or the like.Solid carrier can comprise that one or more maybe be simultaneously as sweetener, lubricant, solubilizing agent, suspension agent, filler, glidant, compression aid, the material of tackiness agent or tablet-disintegrating agent; It can also be an encapsulating material.In powder, carrier is pulverizing solid, and it mixes with pulverizing activeconstituents.Activeconstituents and the carrier with necessary compression property are with suitable mixed, with the shape and the size compression of needs in tablet.Powder and tablet preferably comprise 99% activeconstituents at the most.Suitable solid carrier comprises, for example, and calcium phosphate, Magnesium Stearate, talcum, sugar, lactose, dextrin, starch, gel, Mierocrystalline cellulose, methylcellulose gum, sodium carboxymethyl-cellulose, Vinylpyrrolidone polymer alkane ketone, low melt wax and ion exchange resin.
Exemplary of liquid carriers comprises syrup, peanut oil, and sweet oil, water, or the like.Liquid vehicle is used to prepare solution, suspension-s, emulsion, syrup, the compsn of tincture and sealing.Activeconstituents can dissolve or be suspended in pharmaceutically acceptable liquid vehicle such as water, organic solvent, the mixture of the two or pharmaceutically acceptable oils or fat.Liquid vehicle can comprise other suitable medicated premix such as solubilizing agent, emulsifying agent, and buffer reagent, sanitas, sweetener, sweetener, suspension agent, thickening material, pigment, viscosity modifier is stablized shape or osmotic pressure-regulator.The suitable example that is used for the liquid vehicle of oral and administered parenterally comprises that water (partly comprises as above-mentioned additive; Derivatived cellulose for example; The preferably carboxymethyl cellulose sodium salt solution); Alcohol (comprising monohydroxy-alcohol and polyvalent alcohol, for example terepthaloyl moietie) and their verivate, and oils (for example fractionated coconut oil and peanut oil).The carrier that is used for administered parenterally can also be grease such as OE and sec.-propyl myristate.Aseptic liquid vehicle is used for the aseptic fluid composition of administered parenterally.The liquid vehicle that is used for pressurized compositions can be halohydrocarbon or other pharmaceutically acceptable propelling agents.Sterile solution or aaerosol solution composition of liquid medicine can be used for, for example, and intravenously, intramuscular, intraperitoneal or subcutaneous injection.But single pushes or injection gradually during injection, goes into 30 minutes the interior perfusion of passages through which vital energy circulates.This compound can also be with the form oral administration of liquid or solids compsn.
Carrier or vehicle can comprise time lag material known in the art, like glyceryl monostearate or distearin, also can comprise wax, TKK 021, light propyl methocel, methyl methacrylate or the like.When preparation is used for when oral, generally acknowledge that 0.01% tween 80 among the PHOSALPG-50 is used for the preparation of the acceptable oral preparation of other compounds, can be adapted to the preparation of all cpds of the present invention.Can use medicament forms miscellaneous when giving The compounds of this invention.If the use solid carrier, preparation can be tablet, is placed into powder or piller form or lozenge or lozenge form in the hard capsule.The amount of solid carrier changes to a great extent, but preferably from about 25mg to about 1.0g.If the use liquid vehicle, preparation can be syrup, emulsion, soft capsule, aseptic injectable solution or suspension-s in the liquid suspension of peace bottle or bottle or non-water.
In order to obtain stable water miscible formulation, can compound or its pharmacy acceptable salt be dissolved in the organic or inorganic aqueous acid, 0.3M succsinic acid or citric acid solution.Optionally, the tart verivate can be dissolved in suitable basic soln.If can not get soluble form, can compound be dissolved in suitable cosolvent or their combination.The example of suitable cosolvent like this includes but are not limited to, and concentration range is from the ethanol of 0-60% TV, Ucar 35, Liquid Macrogol, polysorbate 80, glycerine, polyoxyethylene fatty acid ester, Fatty Alcohol(C12-C14 and C12-C18) or the light fatty ester of glycerine or the like.
Various release systems are known and can be used for the administration of compound or other various preparations, and these preparations comprise tablet, capsule, and injectable solution, the capsule in the liposome, particulate, microcapsule, or the like.The method of introducing includes, but are not limited to skin, intracutaneous, intramuscular, endoperitoneal, intravenous, subcutaneous, nasal cavity, lung, peridural, eyes with (preferred usually) oral route.Compound can through any easily or other suitable administration; For example through injecting or bolus injection; Through epithelium or the mucous membrane circuit (for example; Oral mucosa, rectum and intestines mucosa, or the like) absorb or the support through carrying medicament and can be in other biological promoting agent administration together.Can whole body or topical.Be used for nose, when the treatment of segmental bronchus or lung disease or prevention, preferred route of administration is oral, nasal administration or segmental bronchus smoke substance or atomizer.
Description of drawings
Fig. 1 is the H-NMR collection of illustrative plates of N-(5-(4-chloro-phenyl-)-furfuryl)-4-chlorobenzamide (3b);
Fig. 2 is the H-NMR collection of illustrative plates of N-benzyl-5-(4-chloro-phenyl-)-2-furylamine (5b).
Embodiment
Following embodiment can make those skilled in the art more fully understand the present invention, but does not limit the present invention in any way.
The preparation of instance one: N-(5-(4-chloro-phenyl-)-furfuryl)-4-chlorobenzamide (3b):
The preparation (2b) of 5-(4-chloro-phenyl-)-2-furylamine hydrochloride
With p-Chlorobenzoic acid amide (1.28g, 10.0mmol) add hydrochloric acid (25.0mL, 4.8mol/L) in, and heated and stirred after dissolving back question response liquid is cooled to room temperature naturally, places cryosel to bathe to dissolving, and is cooled to below 0 ℃, the adularescent solid is separated out.(10.0ml, 1mol/L), solution is clarified gradually, finishes, and keeps continuing below 0 ℃ to stir 10 minutes, gets the p-Chlorobenzoic acid amide diazonium salt in reaction flask, to drip sodium nitrite solution gradually.In above-mentioned solution, drip chaff amine (1.27g, 13.0mmol) and the cuprous chloride aqueous solution (10.0ml 0.2mol/L), lasts 0.5 hour.After dropwising, rise to room temperature naturally.Nitrogen gas generation is constantly arranged in the reaction process, have brown materials to generate, react 30 hours, react completely stopped reaction to no longer including nitrogen gas generation.Filter, filter cake is used recrystallizing methanol at last with solution of potassium carbonate, petroleum ether, and the adularescent solid is separated out, and filters, and gets off-white color solid 0.50g after the drying, and productive rate is 20.48%.
The preparation (3b) of N-(5-(4-chloro-phenyl-)-furfuryl)-4-chlorobenzamide:
(0.16g 0.66mmol) joins in the anhydrous tetrahydro furan (20mL), places ice bath to make its temperature be lower than 0 ℃, and stirring and dissolving drips triethylamine (1mL) in reaction flask, the solution muddy shape that is white in color with 5-(4-chloro-phenyl-)-2-furylamine.(0.16g 0.91mmol), drips and finishes, and keeps continuing below 0 ℃ to stir 10 minutes, moves to room temperature again, reacts 10 hours, reacts completely stopped reaction slowly to drip parachlorobenzoyl chloride to above-mentioned solution.Add 50mL water, solution has muddy the change to clarify, and becomes muddy subsequently again, crosses and filters yellow solid, uses recrystallizing methanol, filters, and filter cake is the off-white color solid, gets 0.29g.Productive rate is 79.1%.mp：168℃～171℃。It is as shown in Figure 1,
1H-NMR (DMSO-d
6, 600Hz) δ: 4.52 (d, 2H, J=6.6Hz), 6.41 (d, 1H, J=3.0Hz), 6.93 (d; 1H, J=3.6Hz), 7.46 (d, 2H, J=7.8Hz), 7.54 (d, 2H, J=8.4Hz); 7.67 (d, 2H, J=8.4Hz), 7.90 (d, 2H, 8.4Hz), 9.10 (s, 1H).
Instance two: the preparation of N-benzyl-5-(4-chloro-phenyl-)-2-furylamine (5b):
The preparation (4b) of 5-(4-chloro-phenyl-)-2 furan carboxyaldehyde
With p-Chlorobenzoic acid amide (1.28g, 10.0mmol) add hydrochloric acid (25.0mL, 4.8mol/L) in, and heated and stirred after dissolving back question response liquid is cooled to room temperature naturally, places cryosel to bathe to dissolving, the adularescent solid is separated out.(10.0ml, 1mol/L), solution is clarified gradually, finishes to continue to stir 10 minutes, gets the p-Chlorobenzoic acid amide diazonium salt in reaction flask, to drip sodium nitrite solution gradually.In above-mentioned solution, drip furfural (1.44g, 15.0mmol) and the cuprous chloride aqueous solution (10.0ml 0.2mol/L), lasts 0.5 hour.After dropwising, rise to room temperature naturally.Constantly there is nitrogen to emit in the reaction process, and has yellow substance to generate.React and emitted the back stopped reaction to no longer including nitrogen in 10 hours, filter, filter cake is used recrystallizing methanol at last with solution of potassium carbonate, petroleum ether, has golden yellow solid to separate out, filter, after the drying golden yellow solid 0.60g.Yield is 29.00%.
The preparation (5b) of N-benzyl-5-(4-chloro-phenyl-)-2-furylamine hydrochloride
With 5-(4-chloro-phenyl-)-2 furan carboxyaldehyde (0.2g 1.0mmol) joins in the 20mL methyl alcohol, ultrasonic hydrotropy, under the room temperature condition, (0.15g 1.4mmol), drips and finishes, and moves to and continues reaction in 40 ℃ of oil baths, and reaction lasts 3 hours in reaction flask, slowly to drip benzylamine.Question response fully after, shift out after oil bath is cooled to room temperature naturally, place cryosel to bathe; Be cooled to below 0 ℃, gradation add block Peng Qinghuana (0.062g, 1.5mmol); Finish, keep continuing below 0 ℃ to stir 10 minutes, move to room temperature again; Continue reaction 10 hours, react completely stopped reaction.Vacuum is drained, and gets yellow solid, column chromatography, and (stationary phase of column chromatography is a silica gel to gradient elution, and moving phase is sherwood oil: ETHYLE ACETATE=20: 1～2: 1; ), collect principal constituent, vacuum drain faint yellow oily thing.Add an amount of hydrogenchloride-ethanolic soln to above-mentioned oily matter, separate out the pale pink solid, filter, get off-white color solid 0.27g.Yield is 83.46%.mp?233℃～234℃。It is as shown in Figure 2,
1H-NMR (DMSO-d
6, 600Hz) δ: 4.19 (s, 2H), 4.26 (s, 2H), 6.76 (d, 1H, J=3.6Hz), 7.05 (d, 1H, J=3.0Hz), 7.41～7.46 (m, 3H), 7.52 (d, 2H, J=8.4Hz), 7.57 (m, 2H), 7.78 (m, 2H), 9.9 (s, 2H).
Biological activity determination:
Active testing is selected Vibrio harveyi MM32 bacterial strain for use, measures its luminous intensity and calculates IC
50
Table one: furan compound suppresses the activity of Vibrio harveyi AI-2 type quorum sensing
Annotate: numerical value is the MV of three tests in the table.IC
50: the concentration that makes the luminous reduction by 50% of Vibrio harveyi.
Above-mentioned 24 compounds are carried out screening active ingredients, and the activity of their anti-Vibrio harveyi AI-2 type quorum sensing is listed in the table one, and compares with KM.
Can know by table one, 3d-e, 3h-i, 5a, 5d, 5h, 5j-k, 5m, 5o,, have better inhibited activity, wherein the 3h activity is best, its IC
50Be 7.4 ± 1.7 μ M, compound 3a-c, 3f, 5c, 5f-g are because the bad data that do not measure of solvability.This shows that general formula (II) series is better than the compound of general formula (I) series, wherein aromatic nucleus R
1Substituting group the bromine activity slightly is better than 2, the 4-dichloro is two to be replaced and the chlorine list is replaced.The activity of aromatic nucleus Ar: 3-pyridine ≈ 2-furans＞4-chloro-phenyl-.2-Cl＞4-Cl＞3-methoxyl group＞H＞4-F when R1 is the replacement of contraposition list.
Activity research shows that it is active that above-mentioned furfuran compound has the induction of the AI-2 of inhibition type colony, is the AI-2 type colony induction suppressor factor of novel structure, and class is used as the lead compound of antibacterials.
Furfuran compound of the present invention is as the application of AI-2 type colony induction suppressor factor, and specifically, the medicine of infectation of bacteria is treated in preparation as AI-2 type colony induction suppressor factor.
A kind of antibacterial combination comprises furfuran compound of the present invention.
Claims (10)
1. a furfuran compound has general structure (I), or general structure (II) or its hydrochloride
Wherein, Ar
1Be various substituted aromatic rings, Ar
2Be various substituted aromatic rings, Ar
3Be various substituted aromatic rings.
2. a kind of furfuran compound according to claim 1 is characterized in that, wherein Ar
1Be 2,4 dichloro benzene base, 4-chloro-phenyl-or 4-bromophenyl; Ar
2Be phenyl, 4-fluorophenyl, 2-chloro-phenyl-, 4-chloro-phenyl-or 3-p-methoxy-phenyl; Ar
3Be pyridine, 4-chloro-phenyl-or furans.
3. a kind of furfuran compound according to claim 1 is characterized in that, is following compound:
N-(5-(2,4 dichloro benzene base)-furfuryl)-4-chlorobenzamide,
N-(5-(4-chloro-phenyl-)-furfuryl)-4-chlorobenzamide,
N-(5-(4-bromophenyl)-furfuryl)-4-chlorobenzamide,
N-(5-(2,4 dichloro benzene base)-furfuryl)-furoamide,
N-(5-(4-chloro-phenyl-)-furfuryl)-furoamide,
N-(5-(4-bromophenyl)-furfuryl)-furoamide,
N-(5-(2,4 dichloro benzene base)-furfuryl)-vitamin PP,
N-(5-(4-chloro-phenyl-)-furfuryl)-vitamin PP,
N-(5-(4-bromophenyl)-furfuryl)-vitamin PP,
N-benzyl-5-(2,4 dichloro benzene base)-2-furylamine hydrochloride,
N-benzyl-5-(4-chloro-phenyl-)-2-furylamine hydrochloride,
N-benzyl-5-(4-bromophenyl)-2-furylamine hydrochloride,
N-4-luorobenzyl-5-(2,4 dichloro benzene base)-2-furylamine hydrochloride,
N-4-luorobenzyl-5-(4-chloro-phenyl-)-2-furylamine hydrochloride,
N-4-luorobenzyl-5-(4-bromophenyl)-2-furylamine hydrochloride,
N-2-benzyl chloride base-5-(2,4 dichloro benzene base)-2-furylamine hydrochloride,
N-2-benzyl chloride base-5-(4-chloro-phenyl-)-2-furylamine hydrochloride,
N-2-benzyl chloride base-5-(4-bromophenyl)-2-furylamine hydrochloride,
N-4-benzyl chloride base-5-(2,4 dichloro benzene base)-2-furylamine hydrochloride,
N-4-benzyl chloride base-5-(4-chloro-phenyl-)-2-furylamine hydrochloride,
N-4-benzyl chloride base-5-(4-bromophenyl)-2-furylamine hydrochloride,
N-3-methoxy-benzyl-5-(2,4 dichloro benzene base)-2-furylamine hydrochloride,
N-3-methoxy-benzyl-5-(4-chloro-phenyl-)-2-furylamine hydrochloride,
N-3-methoxy-benzyl-5-(4-bromophenyl)-2-furylamine hydrochloride.
4. the preparation method of the described a kind of furfuran compound of claim 1, wherein:
The preparation method of general formula I may further comprise the steps:
(1) with the substituted aniline raw material, at acidic conditions and NaNO
2Effect generates diazonium salt down, under the cuprous chloride effect, generates benzofurane formaldehyde with furfural generation linked reaction then;
(2) the substituted benzylamine generation of benzofurane formaldehyde and aromatic ring nucleophilic addition gets azomethine, generates target compound or continues to make it into hydrochloride through sodium borohydride reduction;
The preparation method of general formula I I may further comprise the steps:
(1) with the substituted aniline raw material, at acidic conditions and NaNO
2Effect generates diazonium salt down, under the cuprous chloride effect, generates the benzofurane methylamine hydrochloride with chaff amine generation linked reaction then;
(2) fragrant formyl chloride is dissolved in the THF, slowly drips in the dichloromethane solution of benzofurane methylamine hydrochloride and triethylamine again, stirring reaction obtains target compound through conventional means separation and purification again.
5. the preparation method of a kind of furfuran compound as claimed in claim 4, wherein:
The preparation method of general formula I is specially:
(1) the 10.0mmol substituted aniline being added 25.0mL concentration is in the hydrochloric acid of 4.8mol/L, and extremely dissolving of heated and stirred, after dissolving back question response liquid is cooled to room temperature naturally, places cryosel to bathe, and the adularescent solid is separated out; In reaction flask, drip 10.0ml 1mol/L sodium nitrite solution gradually, solution is clarified gradually, finishes to continue to stir 10 minutes, gets the substituted aniline diazonium salt; In above-mentioned solution, drip 15.0mmol furfural and 10mL, the 0.2mol/L cuprous chloride aqueous solution lasts 0.5 hour; After dropwising, rise to room temperature naturally; React and emitted the back stopped reaction to no longer including nitrogen in 10 hours, filter, filter cake is used recrystallizing methanol at last with unsaturated carbonate potassium solution, petroleum ether, promptly obtains benzofurane formaldehyde;
(2) 1.0mmol benzofurane formaldehyde is joined in the 20mL methyl alcohol, ultrasonic hydrotropy under the room temperature condition, slowly drips the substituted benzylamine of 1.4mmol aromatic ring in reaction flask, drip and finish, and moves to and continues reaction in 40 ℃ of oil baths, and reaction lasts 3 hours; Then, shift out after oil bath is cooled to room temperature naturally, place cryosel to bathe, be cooled to below 0 ℃, gradation adds the 1.5mmol Peng Qinghuana, finishes, and keeps continuing below 0 ℃ to stir 10 minutes, moves to room temperature again, continues reaction 10 hours, reacts completely stopped reaction; Vacuum is drained, and gets yellow solid, and column chromatography gets faint yellow oily thing, and the stationary phase of column chromatography is a silica gel, and moving phase is sherwood oil: ETHYLE ACETATE=20: 1～2: 1; Add saturated hydrogenchloride-ethanolic soln to above-mentioned oily matter, separate out white solid; Filter cake obtains the target compound shown in the general formula I with the ETHYLE ACETATE washing;
The preparation method of general formula I I is specially:
(1) the 10.0mmol substituted aniline is added 25.0mL, in the 4.8mol/L hydrochloric acid, and extremely dissolving of heated and stirred, after dissolving back question response liquid is cooled to room temperature naturally, place cryosel to bathe, be cooled to below 0 ℃, the adularescent solid is separated out; In reaction flask, drip 10.0ml gradually, the 1mol/L sodium nitrite solution, solution is clarified gradually, finishes, and keeps continuing below 0 ℃ to stir 10 minutes, gets diazonium salt; In above-mentioned solution, drip 13.0mmol chaff amine, and 10mL, the 0.2mol/L cuprous chloride aqueous solution lasts 0.5 hour; After dropwising, rise to room temperature naturally; Nitrogen gas generation is constantly arranged in the reaction process, have brown materials to generate, react 30 hours, react completely stopped reaction to no longer including nitrogen gas generation; Filter, filter cake is used recrystallizing methanol at last with unsaturated carbonate potassium solution, petroleum ether, promptly obtains the benzofurane methylamine hydrochloride;
(2) 0.66mmol benzofurane methylamine hydrochloride is joined in the 20mL anhydrous tetrahydro furan, place ice bath to make its temperature be lower than 0 ℃, stirring and dissolving drips the 1mL triethylamine in reaction flask, the solution muddy shape that is white in color; Slowly drip 0.91mmol fragrance formyl chloride to above-mentioned solution, drip and finish, keep continuing below 0 ℃ to stir 10 minutes, move to room temperature again, reacted 10 hours, react completely stopped reaction; Add 50mL water, solution becomes clarification by muddiness, becomes muddy subsequently again, crosses and filters yellow solid, uses recrystallizing methanol, is the target compound shown in the general formula I I.
6. according to the preparation method of claim 4 or 5 described a kind of furfuran compounds, it is characterized in that said substituted aniline is selected from 2,4 dichloro aniline, 4-chloroaniline or 4-bromaniline.
7. according to the preparation method of claim 4 or 5 described a kind of furfuran compounds, it is characterized in that the substituted benzylamine of said aromatic ring is selected from benzylamine, 4-flunamine, 2-chlorobenzylamine, 4-chlorobenzylamine or 3-methoxybenzylamine.
8. according to the preparation method of claim 4 or 5 described a kind of furfuran compounds, it is characterized in that said fragrant formyl chloride is selected from parachlorobenzoyl chloride, furoyl chloride or nicotinoyl chlorine.
9. the application of each described a kind of furfuran compound of claim 1-3 in the medicine of the anti-AI-2 quorum sensing of preparation.
10. an anti-AI-2 quorum sensing pharmaceutical composition comprises like each described furfuran compound of claim 1-3 and one or more pharmaceutically acceptable carriers or vehicle.
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| CN106635446A (en) * | 2016-09-26 | 2017-05-10 | 浙江工商大学 | Biological film cleaner, preparation thereof and application of cleaner |
| CN107602512A (en) * | 2017-09-25 | 2018-01-19 | 南昌大学 | A kind of method that one kettle way prepares N (5 methyl furfuryl group) aniline |
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| CN106635446A (en) * | 2016-09-26 | 2017-05-10 | 浙江工商大学 | Biological film cleaner, preparation thereof and application of cleaner |
| CN106635446B (en) * | 2016-09-26 | 2019-08-13 | 浙江工商大学 | A kind of biomembrane detergent and its preparation and application |
| CN107602512A (en) * | 2017-09-25 | 2018-01-19 | 南昌大学 | A kind of method that one kettle way prepares N (5 methyl furfuryl group) aniline |
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